RRC ID 74281
Author Ishikawa K, Ishii M, Yaguchi T, Katada T, Ichinose K, Ohata S.
Title epi-Aszonalenin B from Aspergillus novofumigatus inhibits NF-κB activity induced by ZFTA-RELA fusion protein that drives ependymoma.
Journal Biochem Biophys Res Commun
Abstract Nuclear factor-kappa B (NF-κB) signaling is an intracellular signaling pathway involved in inflammatory responses and the pathogenesis of various cancers, including ependymoma, which is a rare and chemotherapy-resistant glioma. Several isoforms of fusion proteins that consist of a nuclear protein, zinc finger translocation associated (ZFTA), and RELA (ZFTA-RELA), an NF-κB-signaling effector transcription factor, cause excessive activation of the NF-κB signaling pathway and result in supratentorial ependymomas (ST-EPN-RELA). As inhibitors of NF-κB activity induced by ZFTA-RELA are expected to be therapeutic agents for ST-EPN-RELA, we established an NF-κB responsive luciferase reporter cell line that expresses the most common isoform of ZFTA-RELA in a doxycycline-dependent manner. Using this reporter cell line, we screened fungus extracts for compounds that inhibit the NF-κB activity induced by ZFTA-RELA expression and identified aszonalenin, an alkaloid from Aspergillus novofumigatus. We also purified analogs of aszonalenin, namely acetylaszonalenin and epi-aszonalenin B and C. In a luciferase assay using cells constitutively expressing luciferase (counter assay), acetylaszonalenin and epi-aszonalenin C showed non-specific inhibition of the luciferase activity. Aszonalenin and epi-aszonalenin B inhibited the NF-κB responsive luciferase activity by expressing ZFTA-RELA more strongly than the luciferase activity in the counter assay. The upregulation of endogenous NF-κB responsive genes, such as CCND1, ICAM1, and L1CAM, by ZFTA-RELA expression was inhibited by epi-aszonalenin B, but not by aszonalenin. This study suggests that epi-aszonalenin B may be a lead compound for the therapeutic development of ST-EPN-RELA.
Volume 596
Pages 104-110
Published 2022-3-12
DOI 10.1016/j.bbrc.2022.01.076
PII S0006-291X(22)00096-1
PMID 35131506
MeSH Aspergillus / chemistry* Blotting, Western Cyclin D1 / genetics Cyclin D1 / metabolism Doxycycline / pharmacology Ependymoma / genetics* Ependymoma / metabolism Ependymoma / pathology Gene Expression Regulation, Neoplastic / drug effects HEK293 Cells HeLa Cells Humans Indole Alkaloids / chemistry Indole Alkaloids / pharmacology* Intercellular Adhesion Molecule-1 Molecular Structure NF-kappa B / antagonists & inhibitors* NF-kappa B / metabolism Neural Cell Adhesion Molecule L1 / genetics Neural Cell Adhesion Molecule L1 / metabolism Nuclear Proteins / genetics* Nuclear Proteins / metabolism Oncogene Proteins, Fusion / genetics* Oncogene Proteins, Fusion / metabolism Reverse Transcriptase Polymerase Chain Reaction Transcription Factor RelA / genetics* Transcription Factor RelA / metabolism
IF 2.985
Pathogenic eukaryotic microorganisms Aspergillus novofumigatus IFM 55215